As many as one in ten adults in the UK have some form of liver disease (British Liver Trust. Alcohol and liver disease. Ringwood: British Liver Trust, 2006). Liver disease is currently the fifth most common cause of mortality for both men and women (Department of Health. Quality Strategy Team Report on Liver Disease: A scoping study into the nature and burden of the disease, 2006). However, whilst the mortality rates for the other four major causes of death are falling, the trend for liver disease is rising in both sexes at an alarming rate there has been a five-fold increase in the prevalence of liver cirrhosis in the last 30 years. The current childhood obesity epidemic, increasing alcohol misuse and viral hepatitis are all contributing to this. Moreover, non-alcoholic fatty liver disease (NAFLD) doubles the risk of cardiovascular mortality (Long-term follow-up of patients with NAFLD and elevated liver enzymes. Ekstedt M, et al. Hepatology 2006; 44: 865).
The problem with liver disease is that often symptoms of the disease are not apparent until the disease reaches an advanced stage. Thus, there is a pressing need for a reliable diagnostic tool for liver disease to identify early disease and target therapies to those patients that may benefit (e.g., antiviral therapy in progressive hepatitis C, weight reduction surgery in fatty liver disease).
The current accepted practice, or “gold standard”, for diagnosing liver disease is an ultrasound-guided liver biopsy. This is less than ideal as there is a small but significant complication risk (1:1000 of severe bleeding, especially in coagulopathic patients). Furthermore, only 0.002% of the liver is examined, and there is great intra and inter-observer variability in histological interpretation (see, e.g., Sampling error and intra-observer variation in liver biopsy in patients with chronic HCV infection. Regev A et al, Am J Gastroenterol. 2002 October; 97(10):2614-8. Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies. Janiec D J et al, Obes Surg. 2005 April; 15(4):497-501. Assessment of Hepatic Steatosis by Expert Pathologists: The End of a Gold Standard. El Badry A M et al, Annals of Surgery 250(5), November 2009, 691-697).
There are few non-invasive diagnostic alternatives for liver disease. Ultrasonography is not specific, is not sensitive in early disease, and is of limited efficacy in obese patients. Transcutaneous elastography can aid in quantifying fibrosis, but is also of limited use in large patients due to reduced acoustic windows. Magnetic resonance (MR) elastography is superior, but expensive, operator dependant and not disease specific.
There are currently no clinical magnetic resonance (MR) protocols for the diagnosis of parenchymal liver disease. Previously published studies have concluded, for example, that there is no justification for the use of proton nuclear magnetic resonance imaging techniques or the in vivo measurement of hepatic T1 relaxation time. (“MRI of parenchymal liver disease.”, Clin. Radiol. 1987 sep; 38 (5): 495-502; Aisen et al., “Detection of liver fibrosis with magnetic cross-relaxation.”, Magn. Reson. Med. 1994 May; 31 (5): 551-6; Alanen et al., “MR and magnetisation transfer imaging in cirrhotic and fatty livers.” Acta. Radiol., 1998 July; 39 (4): 434-9). For a clinically useful tool, further refinement in MR imaging to assess parenchymal tissue fibrosis has been desired to allow differentiation between NAFLD, which is relatively benign, and non-alcoholic steatohepatitis (NASH), which has a worse prognosis and is more strongly linked to coronary artery disease.
Several murine models of liver disease have shown that metabolic dysregulation can lead to steatosis and fibrosis. These include genetic models (e.g., leptin-deficient mouse) and diet-manipulated models (e.g., choline deficient mouse, Western high fat diet mouse). Promisingly, quantitative MR imaging & spectroscopic analysis of liver fat have been validated against post-mortem studies in these models (Quantification of Hepatic Steatosis with 3T MR Imaging: Validation in ob/ob Mice. Hines C D G et al. Radiology; 254: 1; January 2010). However, the phenotypes of these models do not match the human mix of persistent exposure to obesogenic environmental factors (e.g., snacking, sedentary behaviours), chronic Western diet, toxin exposure (alcohol) and slowly progressive fibrosis.
Accordingly, there is a need to address the aforementioned deficiencies and inadequacies.